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J. Biol. Chem., Vol. 280, Issue 43, 36228-36236, October 28, 2005

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Physiological and Receptor-selective Retinoids Modulate Interferon Signaling by Increasing the Expression, Nuclear Localization, and Functional Activity of Interferon Regulatory Factor-1^*

Xin M. Luo and A. Catharine Ross1

From the Department of Nutritional Sciences, Graduate Program in Integrative Biosciences, The Pennsylvania State University, University Park, Pennsylvania 16802

Synergistic actions between all-trans-retinoic acid (atRA) and interferon (IFN) on modulation of cellular functions have been reported both in vitro and in vivo. However, the mechanism of atRA-mediated regulation of IFN signaling is poorly understood. In this study, we have used the human lung epithelial cell line A549 to examine the effect of atRA on IFN-induced expression of IFN regulatory factor-1 (IRF-1), an important transcription factor involved in cell growth and apoptosis, differentiation, and antiviral and antibacterial immune responses. At least 4 h of pretreatment with atRA followed by suboptimal concentrations of IFN induced a faster, higher, and more stable expression of IRF-1 than IFN alone. Actinomycin D completely blocked the induction of IRF-1 by the combination, suggesting regulation at the transcriptional level. Further, we found that activation of signal transducer and activator of transcription-1 was induced more dramatically by atRA and IFN than by IFN alone. Expression of IFN receptor-1 on the cell surface was also increased upon atRA pretreatment. Experiments using receptor-selective retinoids revealed that ligands for retinoic acid receptor- (RAR), including atRA, 9-cis-retinoic acid, and Am580, sequentially increased the levels of IFN receptor-1, activated signal transducer and activator of transcription-1, and IRF-1 and that an RAR antagonist was able to inhibit the effects of atRA and Am580. In addition, atRA pretreatment affected the transcriptional functions of IFN-induced IRF-1, increasing its nuclear localization and DNA binding activity as well as the transcript levels of IRF-1 target genes. These results suggest that atRA, an RAR ligand, regulates IFN-induced IRF-1 by affecting multiple components of the IFN signaling pathway, from the plasma membrane to the nuclear transcription factors.

Received for publication, May 26, 2005 , and in revised form, July 27, 2005.

^* This work was supported by National Institutes of Health Grants DK41479 and CA 90214. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Nutritional Sciences, 126-S Henderson Bldg., University Park, PA 16802. Tel.: 814-865-4721; Fax: 814-865-4723; E-mail: acr6{at}psu.edu.

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